Hou T, Su W, Chacon AN
… +3 more, Lin AH, Guo Z, Gong MC
J Biol Rhythms
· 2025 Feb · PMID 39772880
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Cardiovascular health requires the orchestration of the daily rhythm of blood pressure (BP), which responds to changes in light exposure and dietary patterns. Whether rhythmic light and feeding can modulate daily BP rhyt...Cardiovascular health requires the orchestration of the daily rhythm of blood pressure (BP), which responds to changes in light exposure and dietary patterns. Whether rhythmic light and feeding can modulate daily BP rhythm directly or via modulating intrinsic core clock gene is unknown. Using inducible global knockout mice (iBmal1KO), we explored the impact of rhythmic light, rhythmic feeding, or their combination on various physiological parameters. Daily rhythms of BP, heart rate, and locomotor activity were monitored via radiotelemetry, while food intake patterns were tracked using the BioDAQ system. Respiratory exchange ratio (RER) and energy expenditure (EE) were assessed through indirect calorimetry. In addition, spectrum analysis was employed to analyze spontaneous baroreflex sensitivity and heart rate variability, and urinary norepinephrine excretion was quantified using high-performance liquid chromatography (HPLC). Neither rhythmic feeding nor rhythmic light alone was sufficient to reinstate the daily BP rhythm in arrhythmic iBmal1KO mice. However, combining the light and feeding cues in synchrony partially restored the daily BP rhythm. Interestingly, rhythmic feeding alone robustly reinstated RER and EE rhythms, even without rhythmic light. Similar to BP, the partial reinstatement of the daily rhythms in heart rate and locomotor activity was observed only when rhythmic light and feeding were applied in tandem. Rhythmic light by itself did not restore the light-dark phase difference in baroreflex sensitivity, urinary norepinephrine excretion, or the daily rhythm of heart rate variability. However, rhythmic feeding, alone or in combination with rhythmic light, successfully reinstated the light-dark phase differences in these parameters. In the absence of , the synergy between rhythmic light and feeding can partially restore daily BP rhythm.
J Biol Rhythms
· 2025 Feb · PMID 39722649
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In both diurnal and nocturnal species, the neurons in the suprachiasmatic nucleus (SCN) generate a daily pattern in which the impulse frequency peaks at midday and is lowest during the night. This pattern, common to both...In both diurnal and nocturnal species, the neurons in the suprachiasmatic nucleus (SCN) generate a daily pattern in which the impulse frequency peaks at midday and is lowest during the night. This pattern, common to both day-active and night-active species, has led to the long-standing notion that their functional difference relies merely on a sign reversal in SCN output. However, recent evidence shows that the response of the SCN to the animal's physical activity is opposite in nocturnal and diurnal animals. This finding suggests the presence of additional differences in the circadian system between nocturnal and diurnal species. We therefore attempted to identify these differences in neuronal network organization using the A-B two-oscillator model, which is comprised of Poincaré like oscillators. Based on this model, we infer that in diurnal animals the feedback from physical activity acts on neuronal subpopulations in the SCN that do not receive light input; in contrast, in nocturnal animals, physical activity acts on light-receptive neurons in the SCN in order to produce high-amplitude circadian rhythms.
J Biol Rhythms
· 2025 Feb · PMID 39690979
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Environmental light conditions during development can have long-lasting effects on the physiology and behavior of an animal. Photoperiod, a clear example of environmental light conditions, is detected by and coded in the...Environmental light conditions during development can have long-lasting effects on the physiology and behavior of an animal. Photoperiod, a clear example of environmental light conditions, is detected by and coded in the suprachiasmatic nucleus. It is therefore possible that differences observed in behavior in adulthood after exposure to different perinatal photoperiods are caused by lasting changes in the suprachiasmatic nucleus or alternatively, in other nuclei affected by perinatal photoperiod. It can then be expected that behavior with strong circadian aspects, like rest-activity and sleep, are affected by difference in photoperiod during development as well. To investigate this further, we exposed mice to different photoperiods during their development in the womb until weaning (long: 16 h of light, 8 h of darkness; short: 8 h of light, 16 h of darkness). After weaning, the animals were exposed to a 12 h:12 h light:dark cycle for at least 3 more weeks and some animals were subsequently exposed to constant darkness. We assessed their rest-activity patterns by recording voluntary locomotor activity and used EEG recordings to determine sleep architecture and electroencephalographic spectral density. Perinatal long photoperiod animals showed a shorter duration of locomotor activity than short photoperiod-developed mice in a 12:12 light-dark cycle. This difference disappeared in constant darkness. In the light phase, that is, during the day, perinatal long photoperiod mice spent less time awake and more time in NREM sleep than short photoperiod-developed mice. No effects of perinatal photoperiod were observed in the EEG spectral density or in response to sleep deprivation. We see lasting differences in behavioral locomotor activity and sleep in female and male mice after exposure to different perinatal photoperiods. We conclude that perinatal photoperiod programs a developing mammal for different external conditions and changes brain physiology, which in turn results in long-lasting, possibly even permanent, changes in the sleep and locomotor activity.
The present study aimed to develop a TaqMan genotyping card for molecular chronotype assessment based on a predictive panel of 35 previously identified genetic variants. A reliable TaqMan assay was successfully developed...The present study aimed to develop a TaqMan genotyping card for molecular chronotype assessment based on a predictive panel of 35 previously identified genetic variants. A reliable TaqMan assay was successfully developed for 33 out of the 35 chronotype-predictive variants. The resulting TaqMan genotyping card was utilized to genetically characterize 196 new individuals (in addition to the previously studied 96) and the Morningness-Eveningness Questionnaire was utilized for their phenotypical chronotype assessment. The predictive panel performance was validated on (a) a group of morning and evening individuals (logistic regression model), (b) a representative sample of the original study population also including intermediate chronotypes (linear regression model) and, (c) 25,986 individuals from the Estonian Biobank, for whom Munich Chronotype Questionnaire scores were available. The validation of the morningness-eveningness logistic regression model on 25 morning and 21 evening types resulted in a predictive value of 72%, confirming the reliability of the predictive panel and the success of its conversion into a TaqMan genotyping card. By contrast, the inclusion of intermediate individuals in the model led to a significant decrease in predictive performance (45% on 100 individuals [25 morning, 54 intermediate, and 21 evening]), with intermediate types being the most affected. No significant associations were observed between the genotype panel and chronotype in the Estonian Biobank sample. In conclusion, our genotyping card might represent a promising molecular chronotyping tool for the Italian population. Its performance in other populations is worthy of further study.
Wearable devices have become commonplace tools for tracking behavioral and physiological parameters in real-world settings. Nonetheless, the practical utility of these data for clinical and research applications, such as...Wearable devices have become commonplace tools for tracking behavioral and physiological parameters in real-world settings. Nonetheless, the practical utility of these data for clinical and research applications, such as sleep analysis, is hindered by their noisy, large-scale, and multidimensional characteristics. Here, we develop a neural network algorithm that predicts sleep stages by tracking topological features (TFs) of wearable data and model-driven clock proxies (CPs) reflecting the circadian propensity for sleep. To evaluate its accuracy, we apply it to motion and heart rate data from the Apple Watch worn by young subjects undergoing polysomnography (PSG) and compare the predicted sleep stages with the corresponding ground truth PSG records. The neural network that includes TFs and CPs along with raw wearable data as inputs shows improved performance in classifying Wake/REM/NREM sleep. For example, it shows significant improvements in identifying REM and NREM sleep (AUROC/AUPRC improvements >13% and REM/NREM accuracy improvement of 12%) compared with the neural network using only raw data inputs. We find that this improvement is mainly attributed to the heart rate TFs. To further validate our algorithm on a different population, we test it on elderly subjects from the Multi-ethnic Study of Atherosclerosis cohort. This confirms that TFs and CPs contribute to the improvements in Wake/REM/NREM classification. We next compare the performance of our algorithm with previous state-of-the-art wearable-based sleep scoring algorithms and find that our algorithm outperforms them within and across different populations. This study demonstrates the benefits of combining topological data analysis and mathematical modeling to extract hidden inputs of neural networks from puzzling wearable data.
J Biol Rhythms
· 2025 Apr · PMID 39529231
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My journey into chronobiology began in 1977 with lectures and internships with Wolfgang Engelmann and Hans Erkert at the University of Tübingen in Germany. At that time, the only known animal clock gene was , and the loc...My journey into chronobiology began in 1977 with lectures and internships with Wolfgang Engelmann and Hans Erkert at the University of Tübingen in Germany. At that time, the only known animal clock gene was , and the location and organization of the master circadian clock in the brain was completely unknown for the model insect . I was thus privileged to witness and participate in the research that led us from discovering the first clock gene to identifying the clock network in the fly brain and the putative pathways linking it to behavior and physiology. This article highlights my role in these developments and also shows how the successful use of for studies of circadian rhythms has contributed to the understanding of clock networks in other animals. I also report on my experiences in the German scientific system and hope that my story will be of interest to some of you.
Peralta CM, Feunteun E, Guillaudeau J
… +2 more, Briševac D, Kaiser TS
J Biol Rhythms
· 2025 Feb · PMID 39506296
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Many organisms inhabiting the interface between land and sea have evolved biological clocks corresponding to the period of the semilunar (14.77 days) or the lunar (29.53 days) cycle. Since tidal amplitude is modulated ac...Many organisms inhabiting the interface between land and sea have evolved biological clocks corresponding to the period of the semilunar (14.77 days) or the lunar (29.53 days) cycle. Since tidal amplitude is modulated across the lunar cycle, these circasemilunar or circalunar clocks not only allow organisms to adapt to the lunar cycle, but also to specific tidal situations. Biological clocks are synchronized to external cycles via environmental cues called . Here, we explore how light at night sets the circalunar and circasemilunar clocks of , a marine insect that relies on these clocks to control timing of emergence. We first characterized how moonlight intensity is modulated by the tides by measuring light intensity in the natural habitat of . In laboratory experiments, we then explored how different moonlight treatments set the phase of the clocks of two strains, one with a lunar rhythm and one with a semilunar rhythm. Light intensity alone does not affect the phase of the lunar rhythm. Presenting moonlight during different 2-h or 4-h windows during the night shows that (1) the required duration of moonlight is strain-specific, (2) there are strain-specific moonlight sensitivity windows and (3) timing of moonlight can shift the phase of the lunar rhythm to stay synchronized with the lowest low tides. Experiments simulating natural moonlight patterns confirm that the phase is set by the timing of moonlight. Simulating natural moonlight at field-observed intensities leads to the best synchronization. Taken together, we show that there is a complex and strain-specific integration of intensity, duration and timing of light at night to precisely entrain the lunar and semilunar rhythms. The observed fine-tuning of the rhythms under natural moonlight regimes lays the foundation for a better chronobiological and genetic dissection of the circa(semi)lunar clock in .
J Biol Rhythms
· 2024 Dec · PMID 39449278
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Mammalian circadian biologists commonly characterize the relation between circadian clocks as hierarchical, with the clock in the suprachiasmatic nucleus at the top of the hierarchy. The lineage of research since the sup...Mammalian circadian biologists commonly characterize the relation between circadian clocks as hierarchical, with the clock in the suprachiasmatic nucleus at the top of the hierarchy. The lineage of research since the suprachiasmatic nucleus (SCN) was first identified as in mammals has challenged this perspective, revealing clocks in peripheral tissues, showing that they respond to their own zeitgebers, coordinate oscillations among themselves, and in some cases modify the behavior of the SCN. Increasingly circadian timekeepers appear to constitute a heterarchical network, with control distributed and operating along multiple pathways. One reason for the continued invocation of hierarchy in mammalian circadian biology is that it is difficult to understand how a heterarchical system could operate effectively so as to maintain the organism. Evolved mechanisms, however, need not respect hierarchy and those that have survived have demonstrated the ability of heterarchical organizaton to maintain organisms.
J Biol Rhythms
· 2024 Dec · PMID 39377613
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An autonomous, environmentally synchronizable circadian rhythm is a ubiquitous feature of life on Earth. In multicellular organisms, this rhythm is generated by a transcription-translation feedback loop present in nearly...An autonomous, environmentally synchronizable circadian rhythm is a ubiquitous feature of life on Earth. In multicellular organisms, this rhythm is generated by a transcription-translation feedback loop present in nearly every cell that drives daily expression of thousands of genes in a tissue-dependent manner. Identifying the genes that are under circadian control can elucidate the mechanisms by which physiological processes are coordinated in multicellular organisms. Today, transcriptomic profiling at the single-cell level provides an unprecedented opportunity to understand the function of cell-level clocks. However, while many cycling detection algorithms have been developed to identify genes under circadian control in bulk transcriptomic data, it is not known how best to adapt these algorithms to single-cell RNA seq data. Here, we benchmark commonly used circadian detection methods on their reliability and efficiency when applied to single-cell RNA seq data. Our results provide guidance on adapting existing cycling detection methods to the single-cell domain and elucidate opportunities for more robust and efficient rhythm detection in single-cell data. We also propose a subsampling procedure combined with harmonic regression as an efficient strategy to detect circadian genes in the single-cell setting.
J Biol Rhythms
· 2024 Dec · PMID 39370745
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Mating success depends on many factors, but first of all, a male and a female need to meet at the same place and time. The circadian clock is an endogenous system regulating activity and sex-related behaviors in animals....Mating success depends on many factors, but first of all, a male and a female need to meet at the same place and time. The circadian clock is an endogenous system regulating activity and sex-related behaviors in animals. We studied bumble bees () in which the influence of circadian rhythms on sexual behavior has been little explored. We characterized circadian rhythms in adult emergence and locomotor activity under different illumination regimes for males and gynes (unmated queens). We developed a method to monitor adult emergence from the pupal cocoon and found no circadian rhythms in this behavior for either males or gynes. These results are not consistent with the hypothesis that the circadian clock regulates emergence from the pupa in this species. Consistent with this premise, we found that both gynes and males do not show circadian rhythms in locomotor activity during the first 3 days after pupal emergence, but shortly after developed robust circadian rhythms that are readily shifted by a phase delay in illumination regime. We conclude that the bumble bees do not need strong rhythms in adult emergence and during early adult life in their protected and regulated nest environment, but do need strong activity rhythms for timing flights and mating-related behaviors. Next, we tested the hypothesis that the locomotor activity of males and gynes have a similar phase, which may improve mating success. We found that both males and gynes have strong endogenous circadian rhythms that are entrained by the illumination regime, but males show rhythms at an earlier age, their rhythms are stronger, and their phase is slightly advanced relative to that of gynes. An earlier phase may be advantageous to males competing to mate a receptive gyne. Our results are consistent with the hypothesis that sex-related variations in circadian rhythms is shaped by sexual selection.
Appenroth D, Ravuri CS, Torppa SK
… +3 more, Wood SH, Hazlerigg DG, West AC
J Biol Rhythms
· 2024 Dec · PMID 39370744
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Circadian rhythms synchronize the internal physiology of animals allowing them to anticipate daily changes in their environment. Arctic habitats may diminish the selective advantages of circadian rhythmicity by relaxing...Circadian rhythms synchronize the internal physiology of animals allowing them to anticipate daily changes in their environment. Arctic habitats may diminish the selective advantages of circadian rhythmicity by relaxing daily rhythmic environmental constraints, presenting a valuable opportunity to study the evolution of circadian rhythms. In reindeer, circadian control of locomotor activity and melatonin release is weak or absent, and the molecular clockwork is reportedly non-functional. Here we present new evidence that the circadian clock in cultured reindeer fibroblasts is rhythmic and temperature-compensated. Compared with mouse fibroblasts, however, reindeer fibroblasts have a short free-running period, and temperature cycles have an atypical impact on clock gene regulation. In reindeer cells, and reporters show rapid responses to temperature cycles, with a disintegration of their normal antiphasic relationship. The antiphasic relationship re-emerges immediately after release from temperature cycles, but without complete temperature entrainment and with a marked decline in circadian amplitude. Experiments using promoter reporters with mutated RORE sites showed that a reindeer-like response to temperature cycles can be mimicked in mouse or human cell lines by decoupling reporter activity from ROR/REV-ERB-dependent transcriptional regulation. We suggest that weak coupling between core and secondary circadian feedback loops accounts for the observed behavior of reindeer fibroblasts in vitro. Our findings highlight diversity in how the thermal environment affects the temporal organization of mammals living under different thermoenergetic constraints.
Rhythmic, daily fluctuations in minute ventilation are controlled by the endogenous circadian clock located in the suprachiasmatic nucleus (SCN). While light serves as a potent synchronizer for the SCN, it also influence...Rhythmic, daily fluctuations in minute ventilation are controlled by the endogenous circadian clock located in the suprachiasmatic nucleus (SCN). While light serves as a potent synchronizer for the SCN, it also influences physiology and behavior by activating Brn3b-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). It is currently unclear the extent to which the external light environment shapes daily ventilatory patterns independent of the SCN. To determine the relative influence of environmental light versus circadian timing on the organization of daily rhythms in minute ventilation, we used whole-body plethysmography to measure the breathing of mice housed on a non-entraining T28 cycle (14 h light:14 h dark). Using this protocol, we found that minute ventilation exhibits a ~28-h rhythm with a peak at dark onset that coincides with the light:dark cycle and the animals' locomotor activity. To determine if this 28-h rhythm in minute ventilation was mediated by Brn3b-expressing ipRGCs, we measured the breathing of Brn3bDTA mice housed under the T28 cycle. Brn3bDTA mice lack the Brn3b-expressing ipRGCs that project to many non-SCN brain regions. We found that despite rhythmic light cues occurring on a 28-h basis, Brn3bDTA mice exhibited 24-h rhythms in minute ventilation, locomotor activity, and core body temperature consistent with organization by the SCN. The 24-h minute ventilation rhythm of Brn3bDTA mice was found to be driven predominantly by tidal volume rather than respiratory rate. These data indicate that the external light:dark cycle can directly drive daily patterns in minute ventilation by way of Brn3b-expressing ipRGCs. In addition, these data strongly suggest that the activation of Brn3b-expressing ipRGCs principally organizes daily patterns in breathing and locomotor activity when light:dark cues are presented in opposition to endogenous clock timing.
Animals frequently experience temperature fluctuations in their natural life cycle, including periods of low temperatures below their activity range. For example, poikilothermic animals are known to enter a hibernation-l...Animals frequently experience temperature fluctuations in their natural life cycle, including periods of low temperatures below their activity range. For example, poikilothermic animals are known to enter a hibernation-like state called brumation during transient cooling. However, the knowledge regarding the physiological responses of brumation is limited. Specifically, the impact of exposure to low-temperature conditions outside the range of temperature compensation on the subsequent circadian behavioral rhythms remains unclear. In this study, we investigated the effects of transient cooling on the behavioral circadian rhythm in the non-avian reptile, the bearded dragon (). Under constant light (LL) conditions at 30 °C, the animals exhibited a free-running rhythm, and exposure to low temperatures (4 °C) caused a complete cessation of locomotion. Furthermore, we revealed that the behavioral rhythm after rewarming is determined not by the circadian phase at the onset or the duration of cooling, but by the timing of cooling cessation.
Alzueta E, Gombert-Labedens M, Javitz H
… +13 more, Yuksel D, Perez-Amparan E, Camacho L, Kiss O, de Zambotti M, Sattari N, Alejandro-Pena A, Zhang J, Shuster A, Morehouse A, Simon K, Mednick S, Baker FC
J Biol Rhythms
· 2024 Oct · PMID 39108015
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Most studies about the menstrual cycle are laboratory-based, in small samples, with infrequent sampling, and limited to young individuals. Here, we use wearable and diary-based data to investigate menstrual phase and age...Most studies about the menstrual cycle are laboratory-based, in small samples, with infrequent sampling, and limited to young individuals. Here, we use wearable and diary-based data to investigate menstrual phase and age effects on finger temperature, sleep, heart rate (HR), physical activity, physical symptoms, and mood. A total of 116 healthy females, without menstrual disorders, were enrolled: 67 young (18-35 years, reproductive stage) and 53 midlife (42-55 years, late reproductive to menopause transition). Over one menstrual cycle, participants wore Oura ring Gen2 to detect finger temperature, HR, heart rate variability (root mean square of successive differences between normal heartbeats [RMSSD]), steps, and sleep. They used luteinizing hormone (LH) kits and daily rated sleep, mood, and physical symptoms. A cosinor rhythm analysis was applied to detect menstrual oscillations in temperature. The effect of menstrual cycle phase and group on all other variables was assessed using hierarchical linear models. Finger temperature followed an oscillatory trend indicative of ovulatory cycles in 96 participants. In the midlife group, the temperature rhythm's mesor was higher, but period, amplitude, and number of days between menses and acrophase were similar in both groups. In those with oscillatory temperatures, HR was lowest during menses in both groups. In the young group only, RMSSD was lower in the late-luteal phase than during menses. Overall, RMSSD was lower, and number of daily steps was higher, in the midlife group. No significant menstrual cycle changes were detected in wearable-derived or self-reported measures of sleep efficiency, duration, wake-after-sleep onset, sleep onset latency, or sleep quality. Mood positivity was higher around ovulation, and physical symptoms manifested during menses. Temperature and HR changed across the menstrual cycle; however, sleep measures remained stable in these healthy young and midlife individuals. Further work should investigate over longer periods whether individual- or cluster-specific sleep changes exist, and if a buffering mechanism protects sleep from physiological changes across the menstrual cycle.
J Biol Rhythms
· 2024 Oct · PMID 39096022
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Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of...Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus where it receives retinal input and synchronizes, or entrains, organismal physiology and behavior to the prevailing light cycle. The process of entrainment induces sustained plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the timing, waveform, period, and light resetting properties of the SCN clock and its driven rhythms. To elucidate novel candidate genes for molecular mechanisms of photoperiod plasticity, we performed RNA sequencing on whole SCN dissected from mice raised in long (light:dark [LD] 16:8) and short (LD 8:16) photoperiods. Fewer rhythmic genes were detected in mice subjected to long photoperiod, and in general, the timing of gene expression rhythms was advanced 4-6 h. However, a few genes showed significant delays, including . There were significant changes in the expression of the clock-associated gene and in SCN genes related to light responses, neuropeptides, gamma aminobutyric acid (GABA), ion channels, and serotonin. Particularly striking were differences in the expression of the neuropeptide signaling genes and , as well as convergent regulation of the expression of 3 SCN light response genes, , , and . Transcriptional modulation of and and phase regulation of are compelling candidate molecular mechanisms for plasticity in the SCN light response through their modulation of the critical NMDAR-MAPK/ERK-CREB/CRE light signaling pathway in SCN neurons. Modulation of and may critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity. Data are also available at http://circadianphotoperiodseq.com/, where users can view the expression and rhythmic properties of genes across these photoperiod conditions.
Light is recognized as an important component of the environment for laboratory animals. It supports vision, sets the phase of circadian clocks, and drives wide-ranging adjustments in physiological and behavioral state....Light is recognized as an important component of the environment for laboratory animals. It supports vision, sets the phase of circadian clocks, and drives wide-ranging adjustments in physiological and behavioral state. Manipulating light is meanwhile a key experimental approach in the fields of vision science and chronobiology. Nevertheless, until recently, there has been no consensus on methods for quantifying light as experienced by laboratory animals. Widely adopted practices employ metrics such as illuminance (units = lux) that are designed to quantify light as experienced by human observers. These weight energy across the spectrum according to a spectral sensitivity profile for human vision that is not widely replicated for non-human species. Recently, a Consensus View was published that proposes methods of light measurement and standardization that take account of these species-specific differences in wavelength sensitivity. Here, we draw upon the contents of that consensus to provide simplified advice on light measurement in laboratory mammal experimentation and husbandry and quantitative guidance on what constitutes appropriate lighting for both visual and circadian function.